Aplastic anemia and related disorders

Pancytopenia associated with marrow aplasia is known as aplastic anemia. The diagnosis of severe aplastic anemia rests on the findings of pancytopenia; hypocellular marrow ( Fig. 8.1 ); and two of the following: low reticulocyte count (<1%), neutropenia (<500/μL), or thrombocytopenia (<20,000/μL). Although most cases are seen in adolescents and young adults (ages 15–25 years), cases are also seen in older adults. The marrow failure results from a marked reduction in the number of hematopoietic progenitor cells (granulocyte–macrophage colony-forming unit and erythroid burst-forming unit cells).

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Aplastic anemia (marrow biopsy). Note the extreme hypocellularity with a few scattered, small lymphocytes and plasma cells. Also note the hemosiderosis (brown granular material in histiocytes) that likely reflects the history of multiple transfusions to maintain the hematocrit.

Idiopathic aplastic anemia is an autoimmune condition in which autoreactive T cells suppress hematopoiesis by direct cytotoxicity and production of interferon-γ. Idiopathic aplastic anemia often responds to treatment with immunosuppressive drugs. Aplastic anemia may also be caused by chronic exposure to toxic organic chemicals (benzene, the insecticide lindane, the wood preservative pentachlorophenol, and toluene), drugs (chloramphenicol, ticlopidine, and alkylating agents), and viral infections (Epstein-Barr virus [EBV]). Some cases of aplastic anemia are seen in association with pregnancy, connective tissue disorders (rheumatoid arthritis), and thymoma. No cytogenetic abnormalities are seen in aplastic anemia. Clonal cytogenetic defects indicate the presence of an underlying neoplastic myeloid disorder (myelodysplastic syndrome [MDS], or acute myelogenous leukemia [AML]).

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare intrinsic hemolytic disorder caused by acquired mutations in the Pig-1 gene. Pig-1 is a phosphatidyl-inositol glycosyltransferase that is essential in synthesis of the glycosylphosphatidylinositol (GPI)–linked family of cell membrane proteins. Although many GPI-anchored proteins (in all marrow cells) are deficient in PNH, hemolysis specifically results from deficiency of CD59, the membrane inhibitor of reactive lysis, a GPI-anchored membrane protein that blocks complement-mediated red blood cell (RBC) lysis by preventing incorporation of the lytic terminal complement component C9 into the C5b-8 membrane attack complex. In addition to intermittent bouts of intravascular hemolysis and hemoglobinuria, patients with PNH suffer from recurrent bouts of venous thrombosis most likely caused by complement-mediated activation of GPI-deficient platelets. Neuromuscular symptoms of dysphagia, abdominal pain, and lethargy have been attributed to nitric oxide deficiency mediated by binding of nitric oxide to free plasma hemoglobin to form nitrosohemoglobin . Because marrow cells carrying the PNH defect do not exhibit malignant potential, it is unclear how these cells overgrow the normal marrow. Because PNH is often seen in association with aplastic anemia, it is thought that under these circumstances PNH cells may accumulate as a result of some unexplained survival advantage over normal marrow cells. The diagnosis of PNH can be established either by demonstration of increased sensitivity of PNH red cells to complement-mediated, sucrose-enhanced hemolysis (sucrose lysis test) or acid-enhanced hemolysis (Ham test) or by demonstration of decreased expression of GPI proteins such as CD14, CD16, CD24, CD55, and CD59 on blood cells by flow cytometry. More recently, a flow cytometry test using a recombinant fluorescent-labeled form of bacterial aerolysin (FLAER) has gained popularity for detection of the PNH defect. FLAER binds specifically to GPI-anchored proteins, and demonstration of FLAER-negative blood leukocytes by flow cytometry is characteristic of PNH.

Some forms of aplastic anemia are inherited conditions that present in childhood. The most common hereditary aplastic anemia, Fanconi anemia , is an autosomal recessive condition caused by mutations in genes of the FA pathway . Proteins of the FA pathway repair damage to DNA during DNA replication. Patients typically present in the latter half of the first decade of life with anemia, thrombocytopenia, and mucocutaneous bleeding in association with skeletal anomalies, including short stature and abnormal thumbs. Allogeneic stem cell transplantation is curative. Otherwise, death resulting from marrow failure, myeloid neoplasia, or other cancers usually occurs by 20 years of age. Recently, less severe forms of Fanconi anemia have been recognized in young adults.

Isolated acquired aplasia of erythroid cells is known as pure red cell aplasia (PRCA) . PRCA is characterized by normochromic normocytic anemia, a markedly reduced reticulocyte count, and markedly decreased to absent erythroid cells in the marrow. In adults, acquired PRCA develops in parvovirus B19 infection, MDS, thymoma, or rarely as a drug reaction. Drugs implicated in PRCA include diphenylhydantoin, sulfa drugs, azathioprine, and ribavirin.

The DNA virus parvovirus B19 directly infects erythroid precursors, leading to intramedullary erythroid cell death ( Fig. 8.2 ). Under normal circumstances, parvovirus infection in adults is transient and seldom leads to clinically significant anemia. In immunosuppressed people incapable of producing neutralizing humoral antibody, persistent parvovirus infection leads to chronic PRCA. Acute parvovirus infection in young patients with a chronic hemolytic anemia such as sickle cell disease or hereditary spherocytosis can trigger a transient aplastic crisis by interfering with compensatory erythroid hyperplasia. Transient erythroblastopenia of childhood is a self-limited form of PRCA seen in previously healthy children, presumably secondary to infection with an unrecognized virus. The marrow is normocellular with markedly decreased numbers of erythroid precursors.

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Parvovirus B19 infection (marrow biopsy). Numerous erythroid precursors with pink granular intranuclear viral inclusions are shown. Note the thin rim of nuclear chromatin displaced by the viral inclusion.

Diamond-Blackfan anemia (DBA) , also known as constitutional PRCA , results from defects in erythroid precursors that prevent them from responding to growth signals. In up to 40% of cases, DBA is associated with congenital defects (craniofacial, neck, or thumb). Patients with DBA are at increased risk for development of AML, carcinoma, and MDS. The anemia is normochromic and macrocytic. The reticulocyte count is decreased, and EPO levels are increased. DBA results from sporadic abnormalities at chromosome 19q13 involving the RPS19 gene that encodes for a protein involved in ribosome assembly.

Other forms of aplastic marrow failure include Shwachman-Diamond-Oski syndrome, dyskeratosis congenita, amegakaryocytic thrombocytopenia, severe congenital neutropenia, and cyclic neutropenia. Shwachman-Diamond-Oski syndrome is an autosomal recessive condition marked by short stature, skeletal defects, exocrine pancreatic insufficiency, and cytopenia caused by marrow failure. Patients with this syndrome are at increased risk for MDS and AML. Dyskeratosis congenita is an X-linked or autosomal recessive disorder marked by a triad of lacy reticulated pigmentation of the upper body, leukoplakia, and nail dystrophy. Patients with this disorder develop aplastic anemia, with an increased risk for development of MDS and carcinoma. This disorder is caused by mutations that encode subunits of TERC (telomerase RNA component) gene, thus interfering with proper telomere maintenance and accelerated senescence of highly proliferative tissues such as the bone marrow. Amegakaryocytic thrombocytopenia is an autosomal recessive condition marked by thrombocytopenia and petechial rash in the first year of life, sometimes associated with neurologic and cardiac defects. Aplastic anemia often develops. The disease results from the inheritance of inactivating mutations in c-MPL , the thrombopoietin (TPO) receptor gene. This defect renders the megakaryocytes unresponsive to the growth-promoting properties of TPO. Severe congenital neutropenia (Kostmann syndrome) is an autosomal recessive (sometimes autosomal dominant) condition marked by congenital neutropenia and recurrent life-threatening infections. The condition results from maturation arrest and increased apoptosis of early myeloid precursors (promyelocytes and myelocytes) that carry mutations in ELA-2 (neutrophil elastase), an enzyme normally present in primary granules. The primary treatment is the granulocyte growth factor granulocyte colony-stimulating factor (G-CSF). Kostmann syndrome should be differentiated from other forms of neutropenia that are seen in young children, including viral-induced neutropenia , chronic benign neutropenia of infancy and childhood, and cyclic neutropenia. Viral infection is the most common cause of neutropenia in early childhood. The most common viral infections associated with neutropenia in children are varicella, measles, rubella, hepatitis A and B, Epstein-Barr virus EBV, influenza, parvovirus, and cytomegalovirus. Recovery from virus-induced neutropenia usually follows resolution of active infection. Chronic benign neutropenia of infancy and childhood usually presents within the first 14 months of life. At birth, blood neutrophil counts are normal, but they decline to very low levels with no increase in infection risk. Examination of the bone marrow reveals an increase in immature granulocytes, a result indicative of an appropriate compensatory marrow response. Because antineutrophil antibodies are commonly detected and treatment with steroids is often effective, the disorder is presumably immune in nature. Cyclic neutropenia is a rare autosomal dominant condition that presents most often in the first year of life. The disorder is marked in most cases by 21-day cycles of neutropenia associated with recurrent fever, pharyngitis, and stomatitis. Like severe congenital neutropenia, cyclic neutropenia is associated with mutations of the elastase gene ELA2 . To prevent development of severe chronic dental caries, gingivitis, or stomatitis, patients are treated with G-CSF.